Field of the Invention
We have shown previously that analogs of DCPA retain the ability to block calcium-release activate calcium (CRAC) channels as the parent compound DCPA (N-(3,4-dichlorophenyl)propanamide) but by design, are not metabolized to more toxic N—OH or 6-OH metabolites of the parent compound. The difficulty with these compounds is that they are not water soluble and this makes development of a drug delivery modality more challenging. The compounds of this patent application have been modified at the amide chain with a hydrogen bond acceptor or ionizable functional group like an acid. A compound of this Application is at least one compound selected from the group consisting of 3-(3,4-dichloroanilino)-3-oxopropanoic acid (hereinafter “DCOPA”); N-methyl-DCOPA; N,2-dimethyl-DCOPA; 2-methyl-DCOPA; isobutyl-DCOPA; N-methyl-isobutyl DCOPA; 3-(3,4-bibromoanilino)-3-oxopropanoic acid; and analogs of DCOPA; and analogs of 3-(3,4-dibromoanilino)-3-oxopropanoic acid; and pharmaceutically acceptable salts of these compounds. DCOPA is a more water soluble compound than DCPA. These new compounds of this application inhibit CRAC channels and thus, inhibit osteoclast development and subsequent bone erosion associated with arthritides. Because these new compounds of this application have enhanced solubility, drug delivery will be simplified without sacrificing efficacy. There is currently no drug available to inhibit bone erosion by down-regulating osteoclast development. Bone erosion is the cause of major debilitating effects of arthritides. The compounds of this Application meet this unmet need.
Description of the Background Art
The role of calcium release activated calcium (CRAC) channels is discussed in Zhou et al., “The role of calcium release activated calcium channels in osteoclast differentiation”, J. Cell Physiol 226:1082 (2011).
Analogs of DCPA that inhibit CRAC channels is the subject of a previously filed patent application by WVU, namely, U.S. patent application Ser. No. 13/864,438, filed on Apr. 17, 2013, US Patent Application Publication No. 2013/0303621 A1, having a publication date of Nov. 14, 2013. We have shown that the parent compound, DCPA. inhibits CRAC channels and inhibits development of osteoclasts, significantly reduces the severity of collagen-induced arthritis (CIA) in mice, and inhibits the blood destruction associated with CIA. DCPA and its analogs, e.g., N-methyl-DCPA, are very hydrophobic which presents challenges to developing a drug using these compounds. In comparison to known compounds, the compounds of this patent application are designed having greater solubility while retaining biological activity.
Many thousands of people suffer from various forms of arthritis secondary to inflammatory processes that destroy bone and joints, including rheumatoid arthritis (RA), juvenile RA, arthritis secondary to infections, and idiopathic arthritis. Treatments available for these conditions include anti-inflammatory drugs, e.g., etanercept, antimetabolites, e.g., methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDs, for example ibuprofen) which have significant side effects. However, none of these drugs are effective at preventing bone erosion that occurs in a significant percentage of arthritis patients